1. Field of Invention
This invention includes 2-adenosine propargyl phenyl ether compositions that are useful as A.sub.2A receptor agonists. The compositions of this invention are vasodialating agents that are useful as heart imaging agents that aid in the identification of mammals, and especially humans who are suffering from disorders such poor coronary perfusion which is indicative of coronary artery disease (CAD). The compositions of this invention can also be used as therapeutics for coronary artery disease.
2. Description of the Art
Pharmacological stress is frequently induced with adenosine or dipyridamole in patients with suspected CAD before imaging with T1 scintigraphy or echocardiography. Both drugs effect dilation of the coronary resistance vessels by activation of cell surface A.sub.2 receptors. Although pharmacological stress was originally introduced as a mean of provoking coronary dilation in patients unable to exercise, several studies have shown that the prognostic value of .sup.201 T1 or echocardiographic imaging in patients subjected to pharmacological stress with adenosine of dipyridamole was equivalent to patients subjected to traditional exercise stress tests. However, there is a high incidence of drug-related adverse side effects during pharmacological stress imaging with these drugs such as headache and nausea, that could be improved with new therapeutic agents.
Adenosine A.sub.2B and A.sub.3 receptors are involved in a mast cell degranulation and, therefore, asthmatics are not give the non-specific adenosine agonists to induce a pharmacological stress test. Additionally, adenosine stimulation of the A.sub.1 receptor in the atrium and A-V mode will diminish the S-H interval which can induce AV block. (N. C. Gupto et al.; J. Am Coll. Cardiol; (1992) 19: 248-257). Also, stimulation of the adenosine A1 receptor by adenosine may be responsible for the nausea since the A.sub.1 receptor is found in the intestinal tract. (J. Nicholls et al.; Eur. J. Pharm.(1997) 338(2) 143-150).
Animal data suggests that specific adenosine A.sub.2A subtype receptors on coronary resistance vessels mediate the coronary dilatory responses to adenosine, whereas subtype A.sub.2B receptor stimulation relaxes peripheral vessels (note: the latter lowers systemic blood pressure). As a result there is a need for pharmaceutical compositions that are A.sub.2A receptor agonists that have no pharmacological effect as a result of stimulating the A.sub.1 receptor in vivo. Furthermore, there is a need for A.sub.2A receptor agonists that have a short half-life, and that are well tolerated by patients undergoing pharmacological coronary stress evaluations.